Amifostine (also known as WR-2721) has been shown to be useful as a radiation protectant in cancer patients receiving radiation therapy (Constine et al., 1986, “Protection by WR-2721 of Human Bone Marrow Function Following Irradiation” Int. J. Radia. Oncol. Biol. Phys. 12:1505–8; Liu et al., 1992, “Use of Radiation with or Without WR-2721 in Advanced Rectal Cancer” Cancer 69(11):2820–5; Wadler et al., 1993, “Pilot Trial of Cisplatin, Radiation and WR-2721 in Carcinoma of the Uterine Cervix: A New York Gynecologic Oncology Group Study” J. Clin. Oncol. 11(8):1511–6; Büntzel et al., 1996, “Selective Cytoprotection with Amifostine in Simultaneous Radiochemotherapy of Head Neck Cancer” Ann. Oncol. 7(Suppl.5):81(381P)). Amifostine is a pro-drug that is dephosphorylated at the tissue site by alkaline phosphatase to the free thiol, which is the active metabolite (also known as WR-1065). Once inside the cell, the active free thiol can protect against the toxicities associated with radiation by acting as a scavenger for oxygen free-radicals that are produced by ionizing radiation (Yuhas, 1977, “On the Potential Application of Radioprotective Drugs in Solid Tumor Radiotherapy,” In: Radiation-Drug Interactions in Cancer Management pp. 303–52; Yuhas, 1973, “Radiotherapy of Experimental Lung Tumors in the Presence and Absence of a Radioprotective Drug S-2-(3-Aminopropylamino) thylphosphorothioc Acid (WR-2721)” J. Natl. Cancer Inst. 50:69–78; Philips et al., 1984, “Promise of Radiosensitizers and Radioprotectors in the Treatment of Human Cancer” Cancer Treat. Rep. 68:291–302).
Amifostine's ability to selectively protect normal tissues is based on the differential metabolism and uptake of amifostine into normal tissue versus tumor tissue. Amifostine is rapidly taken up and retained in normal tissues. Differences in capillary and membrane-bound alkaline phosphatase concentration and pH between normal and tumor tissues have been shown to favor the conversion of the pro-drug and uptake of the active form of amifostine, the free thiol, into normal tissues. Coupled with the fact that normal cells concentrate the free thiol at a faster rate than tumors and retain it for longer periods of time, amifostine is able to selectively protect normal tissues against the toxicities associated with radiation without negatively affecting the antitumor response. The marked differences in tissue uptake and retention between normal and tumor tissues produces a temporary state of acquired drug resistance in normal tissues, analogous to that produced by an excess of endogenous glutathione.
For a cytoprotector to be useful in radiation therapy, the compound must be tolerated on a daily basis, up to 4 or 5 days a week for several weeks, prior to the delivery of conventional doses of radiation. McDonald et al. (McDonald, 1994, “Preliminary Results of a Pilot Study Using WR-2721 Before Fractionated Irradiation of Head and Neck to Reduce Salivary Gland Dysfunction” Int. J. Radiat. Oncol. Biol. Phys. 29(4):747–54; McDonald et al., 1995, “Amifostine Preserves the Salivary Gland Function During Irradiation of the Head and Neck” Eur. J. Cancer 31a(Supp. 5):415) have conducted a dose-escalation study of amifostine and radiation in patients with head and neck cancer. These results suggest that daily administration of amifostine (200 mg/m2 via a 6-minute intravenous infusion) prior to radiation protects the salivary gland against the toxicities of radiation.
Amifostine has also been shown to stimulate bone marrow growth, and is currently in Phase II clinical trials as a bone marrow stimulant in patients suffering from myelodysplastic syndrome (List et al., 1996, “Amifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic Syndrome (MDS): Results of a Phase I/II Clinical Trial” Am. J. Hem. 1 (Abstract); List et al., 1996, “Amifostine Promotes in vitro and in vivo Hematopoiesis in Myelodysplastic Syndromes” Chem. Found Sympos. (Abstract); List et al, 1996, “Amifostine Promotes Multilineage Hematopoiesis in Patients with Myelodysplastic Syndrome (MDS): Results of a Phase I/II Clinical Trial,” Abstract, 8th Annual Meeting, American Society of Hematology, Orlando, Fla.). In this study, amifostine is being administered via intravenous infusion.
Intravenous administration of amifostine suffers from several serious drawbacks. First, administering compounds intravenously is extremely inconvenient, particularly when a daily dosing schedule for several weeks, or potentially several months in the case of MDS, is necessary, requiring a skilled practitioner to administer the dose. Second, when administered intravenously, patients suffer from dose-dependent undesirable side-effects such as nausea, vomiting, emesis and hypotension, as well as flushing or feeling of warmth, chills or feeling of coldness, dizziness, somnolence, hiccups and sneezing. A decrease in serum calcium concentration is a known pharmacological effect of intravenously administered amifostine. Allergic reactions ranging from mild skin rashes to rigors have also rarely occurred in conjunction with intravenously administered amifostine. At present, there are no known methods, other than co-administering agents such as anti-emetics, of reducing or avoiding these undesirable side effects. Third, there are related costs associated with intravenous administration, including personnel, equipment and medical measures to attenuate side effects.
The human pharmacokinetic profile of amifostine has been investigated in cancer patients following a single intravenous bolus dose (150 mg/kg) (Shaw et al., 1986, “Human Pharmacokinetics of WR-2721” Int. J. Radiat. Oncol. Biol. Phys. 12:1501–4), a single 15-minute intravenous infusion (up to 910 mg/m2) (Shaw et al., 1988, “Pharmacokineties of WR-2721” Pharmac. Ther. 39:195–201; Shaw et al., 1994, “Pharmacokinetics of Amifostine in Cancer Patients: Evidence for Saturable Metabolism” Proc. Amer. Cos. Clin. Oncol. 13:144; U.S. Bioscience, 1994, “Pharmacokinetics of Single Dose Amifostine (WR-2721; Ethyol)” ETH PK 3) and repeated infusions (up to 910 mg/m2 per dose) (U.S. Bioscience, 1994, “Pharmacokinetics of Double Dose Amifostine (WR-2721; Ethyol) with Corresponding Measurements of WR-1065 in Plasma and Bone Marrow Cells” ETH PK 4). These studies showed that amifostine is rapidly cleared from the plasma with a distribution half-life of less than 1 minute and an elimination half-life of approximately 9 minutes. Less than 10% of amifostine remained in the plasma 6 minutes after intravenous administration. No previous human clinical pharmacokinetic studies have been conducted using either orally or subcutaneously administered amifostine.
Tabachlik reported that the oral administration of amifostine reduced sputum viscosity in cystic fibrosis patients (Tabachnik el al., 1980, “Studics on the Reduction of Sputum Viscosity in Cystic Fibrosis Using an Orally Absorbed Protected Thiol.” J. Pharm. Exp. Ther. 214:246–9; Tabachnik et al., 1982, “Protein Binding of N-2-Mercaptoethyl-1 3-Diaminopropane via Mixed Disulfide Formation After Oral Administration of WR-2721” J. Pharm Exp. Ther. 220:243–6). However, these studies did not demonstrate that this mode of administration reduced adverse side effects commonly associated with intravenously administered amifostine. Furthermore, a study of the pharmacokinetic profile of the admnistered compounds was not conducted in these patients.